Despite combined antiretroviral therapy, HIV-1 associated neurocognitive disorders (HAND) remain highly prevalent in infected patients. HAND progression is associated with chronic inflammatory responses outside and inside of the central nervous system (CNS) driven by low levels of HIV replication, monocyte/macrophage activation, inefficient immune responses and compromise of the blood brain barrier (BBB). Inflammatory mediators and engagement of immune cells migrating into the CNS result in BBB injury. Alcohol misuse (common co-morbidity in HIV infected patients) accelerates HIV progression and HAND. Data obtained in humans and animal models suggest that alcohol promotes neuroinflammation and BBB injury. Therefore, interventions diminishing HIV replication and decreasing chronic inflammation could ameliorate HAND in the setting of alcohol abuse. Cannabinoid receptor 2 (CB2) agonists possess potent anti-inflammatory effects, protect the BBB and suppress HIV infection in macrophages. Although the published studies strongly suggest that CB2 activation may represent a promising novel therapeutic target for HIV infection and HAND, what is missing is the availability of CB2 agonists with optimal pharmacological properties (oral bioavailability, appropriate pharmacokinetics) and absence of major toxicity as tested in relevant `humanized' models of HIV infection and neuroinflammation. Using complimentary expertise in CB2 receptor pharmacology/toxicology (NIAAA intramural research program) and modeling of HIV infection in vitro and in vivo (Temple University) we propose to test a set of novel, highly selective and orall available CB2 agonists assuring quick translation toward clinical application for the treatment of HIV infection. We will first identify selective CB2 agonists with improved pharmacological properties and toxicology profile, and then test their ability to decrease HIV replication in human macrophages, to diminish migration of HIV infected monocytes and to protect the BBB in the setting of alcohol exposure. Lastly, we will evaluate the best CB2 compounds in a `humanized' animal model of HIV infection. This proposal brings together research expertise that will address key HIV and alcohol based research questions that would not otherwise be possible.